Gelatinases A and B are up-regulated in rat lungs by subacute hyperoxia: pathogenetic implications

Am J Pathol. 1998 Sep;153(3):833-44. doi: 10.1016/S0002-9440(10)65625-8.


Subacute hyperoxia may cause basement membrane disruption and subsequent fibrosis. To test the role of extracellular matrix degradation in hyperoxic damage, we analyzed the expression of gelatinases A and B and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in rats exposed to 85% O2. Oxygen-exposed rats were studied at 1, 3, 5, and 7 days, and compared with air-breathing rats. Lung mRNAs assayed by Northern and in situ hybridization showed an up-regulation of lung gelatinases A and B from the 3rd day on. Gelatinase A was localized in alveolar macrophages and in interstitial and alveolar epithelial cells. Gelatinase B mRNA and protein were localized in macrophages and bronchiolar and alveolar epithelial cells. Increased gelatinase A and B activities were demonstrated in bronchoalveolar lavage. TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increase with hyperoxia. To elucidate transcriptional mechanisms for increased gelatinase B expression after hyperoxia, nuclear transcription factor-kappabeta activation was explored. Oxidative stress significantly increased the lung expression of nuclear transcription factor-kappabeta (p65) protein, and nuclear transcription factor-kappabeta activation and increased levels of gelatinases A and B were found in isolated type II alveolar cells obtained from hyperoxic rats. Conceivably, subacute hyperoxia induces excessive gelatinase activity, which may contribute to lung damage.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • Basement Membrane / metabolism
  • Basement Membrane / pathology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Collagenases / genetics
  • Collagenases / metabolism*
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Hyperoxia / enzymology*
  • Hyperoxia / pathology
  • Immunoenzyme Techniques
  • In Situ Hybridization
  • Lung / enzymology*
  • Lung / pathology
  • Male
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • NF-kappa B / analysis
  • NF-kappa B / antagonists & inhibitors
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Specific Pathogen-Free Organisms
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Up-Regulation


  • NF-kappa B
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Collagenases
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9